Adenocarcinoma of the lung is the leading cause of cancer-related death worldwide. Recently, chromosomal rearrangements involving the c-ros oncogene 1 (ROS1) receptor tyrosine kinase (RTK) genes have been described in a variety of multiple human cancers, including non-small-cell lung cancer (NSCLC) (Cancer Genome Atlas Research, Nature, 2014, 511(7511):543-550). Such rearrangements are accompanied by the fusion of a portion of ROS1 that includes its entire tyrosine kinase domain with several partner proteins with resulting ROS1 fusion kinases being constitutively activated and driving cellular transformation (Shaw A. T. et al., N Engl J Med, 2014, 371(21):1963-1971). The kinase domain of ROS1 is known to become constitutively active while driving cellular proliferation along with such rearrangements (Davies K. D. and Doebele R. C., Clin Cancer Res, 2013, 19(15):4040-4045). ROS1 fusion kinases activate growth and survival pathways necessary for the growth and survival of cancer cells, which pathways are reported to include auto-phosphorylation of ROS1 and phosphorylation of AKT, ERK and STAT3 (Davies K. D. and Doebele R. C., Clin Cancer Res, 2013, 19(15):4040-4045). In this context, ROS1 rearrangement defines a distinct molecular subgroup of NSCLC. Rearrangement of genes encoding ROS1 is reported to occur in approximately 1%-2% of NSCLC cancers (Davies K. D. et al., Clin Cancer Res, 2012, 18(17):4570-4579; Davies K. D. and Doebele R. C., Clin Cancer Res, 2013, 19(15):4040-4045). Accordingly, of the estimated 1.5 million new cases of NSCLC worldwide each year, approximately 15,000 may be associated with and driven by oncogenic ROS1 fusions, especially to be found in NSCLC patients who are non-smoker or with light smoking history, of younger age and have histologic features of adenocarcinoma (Shaw A. T. et al., N Engl J Med, 2014, 371(21):1963-1971). The clinical success of targeting oncogenic tyrosine kinases has launched a new area of cancer therapy.
Crizotinib, which is a potent, ATP-competitive small molecule ALK inhibitor has also been used as a ROS1 inhibitor and is currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Although crizotinib shows promising early favorable response in patients with ROS1-rearranged NSCLC, its efficacy is more and more limited due to the development of drug resistance. Hence, ensuring durable response to crizotinib therapy represents an universal challenge as drug resistance proved to be common due to several resistance mechanism observed in patients treated with crizotinib including acquired point mutations, gene amplification and activation of alternative signaling pathways (Davare M. A. et al., Proceedings of the National Academy of Sciences, http://www.pnas.org/cgi/doi/10.1073/pnas. 1515281112; Lee H. J. et al., Cancer Cell, 2014, 26(2):207-221; Lovly C. M. and Shaw A. T., Clin Cancer Res, 2014, 20(9):2249-2256; Rikova K. et al., Cell, 2007, 131(6):1190-1203). Accordingly, patients who responded to crizotinib will eventually experience disease progression despite continued treatment.
Thus, identification of potent ROS1 inhibitors for cancer therapy is necessary (Zou H. Y. et al., Cancer Cell, 2015, 28(1): 70-81). Accordingly, there is a strong need for new compounds which are able to target ROS1 and sufficiently inhibit ROS1 kinase activity, which compounds can, thus, be used for cancer therapy, in particular for treatment of NSCLC.